KR20090057388A - Method for producing succinimide compound - Google Patents
Method for producing succinimide compound Download PDFInfo
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- KR20090057388A KR20090057388A KR1020097005322A KR20097005322A KR20090057388A KR 20090057388 A KR20090057388 A KR 20090057388A KR 1020097005322 A KR1020097005322 A KR 1020097005322A KR 20097005322 A KR20097005322 A KR 20097005322A KR 20090057388 A KR20090057388 A KR 20090057388A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
Abstract
Description
본 발명은, 숙신이미드 화합물의 제조 방법으로, 상게하게는, 저가이고 안전하며 단공정으로 실시 가능하고, 또한 종래에 알려진 제조 방법 보다도 고수율로 숙신이미드 화합물을 제조할 수 있는 방법에 관한 것이다. 또한, 본 발명의 제조 방법에 의해 얻어지는 화합물은 의약품 등의 중간 원료로 이용되는 유용한 화합물이다.The present invention relates to a method for producing a succinimide compound, which is usually inexpensive, safe, and can be carried out in a single step, and to a method for producing a succinimide compound in higher yield than a conventionally known production method. will be. Moreover, the compound obtained by the manufacturing method of this invention is a useful compound used as intermediate raw materials, such as a pharmaceutical.
종래, 숙신이미드 화합물을 제조하는 방법으로는, 시아노초산 에스테르 유도체를 α-할로초산에스테르에 의해 알킬화하고, 그 후, 과산화 수소 등으로 산화하고, 이미드화하는 방법, 및 아미노마론산에스테르 유도체를 α-할로아세트니트릴에 의해 알킬화하고, 그 후 마찬가지로 과산화 수소 등으로 산화하고, 이미드화 하는 방법이 알려져 있다(특허문헌1, 특허문헌2, 비특허문헌1 참조).Conventionally, as a method for producing a succinimide compound, a method of alkylating a cyanoacetic acid ester derivative with α-haloacetic acid ester, then oxidizing with hydrogen peroxide or the like and imidizing the aminomaronic acid ester derivative The method of alkylating with (alpha) -haloacenitrile, and then oxidizing with hydrogen peroxide etc. and imidating similarly is known (refer patent document 1, patent document 2, nonpatent literature 1).
한편, 본 명세서에서 기술하는 것과 동일한 반응 형식인 아미노마론산 유도체와, 할로아세트아미드 유도체와의 반응에서 직접 숙신이미드 화합물을 합성하는 방법에 관해서는 특허문헌1에 기재되어 있다.On the other hand, Patent Document 1 describes a method for synthesizing a succinimide compound directly by reaction between an aminomaronic acid derivative and a haloacetamide derivative, which are in the same reaction format as described herein.
특허문헌1: 일본 특개평 6-192222호 공보Patent Document 1: Japanese Patent Laid-Open No. 6-192222
특허문헌2: 일본 특개평 5-186472호 공보Patent Document 2: Japanese Patent Application Laid-Open No. 5-186472
비특허문헌1: J. Med. Chem.(1998), 41, p.4118-4129[Non-Patent Document 1] J. Med. Chem. (1998), 41, p. 4118-4129
그러나, 시아노초산에스테르 유도체를 α-할로초산 에스테르에 의해 알킬화하고, 그 후 과산화 수소 등으로 산화하고, 이미드화 하는 방법이나 아미노마론산 에스테르 유도체를 α-할로아세트니트릴에 의해 알킬화하고, 그 후, 과산화 수소 등으로 산화하고 이미드화하는 방법은, 공정수가 길고, 과산화물을 이용한다는 점에서 안전성에도 문제가 있는 제조 방법이었다.However, the cyanoacetic acid ester derivative is alkylated with α-haloacetic acid ester, and then oxidized with hydrogen peroxide or the like, and the imidation method or aminomaronic acid ester derivative is alkylated with α-haloacenitrile. The method of oxidizing and imidizing with hydrogen peroxide or the like has a long process number and is a production method having a safety problem in that a peroxide is used.
또한, 할로아세트아미드에서 직접 숙신이미드 화합물을 제조하는 기존의 방법으로는, 목적물인 이미드 화합물의 수율이 낮고(36.5%), 또한 부생성물이 많이 생성되게 되므로 컬럼크로마토그래피에 의한 정제가 필요해져 공업적으로 실용적이지 않았다.In addition, conventional methods for preparing succinimide compounds directly from haloacetamides require low yields (36.5%) of the imide compounds as targets, and a large amount of byproducts. It was not industrially practical.
이로 인해, 종래법에서는 불가능한, 할로아세트아미드에서 직접 숙신이미드 화합물을 고수율, 고순도로 제조할 수 있는 방법이 요구되어 왔다.For this reason, the method which can manufacture succinimide compound directly from haloacetamide in high yield and high purity which is impossible with the conventional method has been calculated | required.
본 발명자들은, 상기 과제를 달성하기 위해 예의 검토를 반복한 결과, 순차 반응 및 부반응을 억제하고, 고수율로 목적 물질을 얻을 수 있는 반응 조건을 발견하였다.MEANS TO SOLVE THE PROBLEM As a result of repeating earnest examination in order to achieve the said subject, the present inventors discovered the reaction conditions which can suppress a sequential reaction and a side reaction, and can obtain a target substance in high yield.
즉, 본 발명은,That is, the present invention,
제1 관점으로, 식(1)In a first aspect, equation (1)
(식중, R1 및 R4는, 각각 독립적으로 직쇄상, 분지상 또는 환상일 수 있는 탄소 원자 수 1 내지 12의 알킬기 또는 치환될 수 있는 탄소 원자 수 6 내지 12의 방향족기를 나타내고, R2 및 R3은, 각각 독립적으로 수소 원자, 직쇄상, 분지상 또는 환상일 수 있는 탄소 원자 수 1 내지 12의 알킬기, 치환될 수 있는 탄소 원자 수 2 내지 6의 아실기, 치환될 수 있는 탄소 원자 수 1 내지 6의 알콕시카르보닐기, 방향환부가 치환될 수 있는 벤질기 또는 방향환부가 치환될 수 있는 벤질옥시카르보닐기를 나타내거나, 또는 R2 및 R3은, 이들이 결합하는 질소 원자와 함께 환을 형성한다.)로 나타내는 아미노마론산에스테르화합물과, (Wherein R 1 and R 4 each independently represent an alkyl group having 1 to 12 carbon atoms which may be linear, branched or cyclic or an aromatic group having 6 to 12 carbon atoms which may be substituted, and R 2 and R 3 is each independently a hydrogen atom, a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, an acyl group having 2 to 6 carbon atoms which may be substituted, or a carbon atom which may be substituted An alkoxycarbonyl group of 1 to 6, a benzyl group which can be substituted with an aromatic ring or a benzyloxycarbonyl group which can be substituted with an aromatic ring, or R 2 and R 3 together with the nitrogen atom to which they are bonded form a ring Aminomaronic acid ester compound represented by.),
식(2)Formula (2)
(식중, X는 할로겐 원자를 나타낸다.)로 나타내는 화합물을 용매 중, 염기 존재 하에서 반응시키는 것에 의한, 식(3)Formula (3) by reacting the compound represented by (wherein X represents a halogen atom) in a solvent in the presence of a base.
(식중, R5는 직쇄상, 분지상 또는 환상일 수 있는 탄소 원자 수 1 내지 12의 알킬기 또는 치환될 수 있는 탄소 원자 수 6 내지 12의 방향족기를 나타내고, R2 및 R3은, 상기 식(1)에서의 정의와 동일한 의미이다.)로 나타내는 숙신이미드 화합물의 제조 방법에 있어, 용매로 알콜, 염기로 알칼리 금속 알콕시드를 이용하는 것을 특징으로 하는 제조 방법.(Wherein R 5 represents an alkyl group having 1 to 12 carbon atoms which may be linear, branched or cyclic or an aromatic group having 6 to 12 carbon atoms which may be substituted, and R 2 and R 3 are represented by the above formula ( In the method for producing a succinimide compound represented by 1), an alcohol and an alkali metal alkoxide are used as the solvent.
제2 관점으로, 상기 용매로 에탄올을 이용하고, 또한 상기 염기로 나트륨에톡시드를 이용하는 것을 특징으로 하는 제1 관점에 기재된 제조 방법.As a 2nd viewpoint, ethanol is used for the said solvent, and sodium ethoxide is used for the said base, The manufacturing method of 1st viewpoint characterized by the above-mentioned.
제3 관점으로, 상기 식(1)로 나타내는 아미노마론산에스테르 화합물이, R1 및 R4가 에틸기를 나타내고, R2가 수소 원자를 나타내고, R3가 벤질옥시카르보닐기를 나타내는 화합물이고, 상기 식(3)으로 나타내는 숙신이미드 화합물이 식(4)From a 3rd viewpoint, the aminomaronic acid ester compound represented by said Formula (1) is a compound in which R <1> and R <4> represent an ethyl group, R <2> represents a hydrogen atom, and R <3> shows a benzyloxycarbonyl group, said formula Succinimide compound represented by (3) is formula (4)
(식중, Et는 에틸기를 나타내고, Ph는 페닐기를 나타낸다.)로 나타내는 화합물인 제1 관점 또는 제2 관점에 기재된 제조 방법,(In the formula, Et represents an ethyl group and Ph represents a phenyl group.) The production method according to the first aspect or the second aspect, which is a compound represented by
에 관한 것이다.It is about.
본 발명의 치환기의 정의는 이하에 나타내는 바와 같다. 단, n-은 노르말을, i-는 이소를, sec-는 2차를, t-는 3차를 각각 나타낸다.The definition of the substituent of this invention is as showing below. N- is normal, i- iso, sec- is secondary, and t- is tertiary.
본 명세서에서 직쇄상, 분지상 또는 환상일 수 있는 탄소 원자 수 1 내지 12의 알킬기는, 1 내지 12개의 탄소 원자로 이루어진 직쇄상, 분지상 또는 환상의 탄화수소기를 나타내고, 예를 들어, 메틸기, 에틸기, n-프로필기, i-프로필기, 시클로프로필기, n-부틸기, i-부틸기, sec-부틸기, t-부틸기, 시클로부틸기, n-펜틸기, 시클로펜틸기, 1-메틸부틸기, 2-메틸부틸기, 3-메틸부틸기, 1-에틸프로필기, 1,1-디메틸프로필기, 1,2-디메틸프로필기, 2,2-디메틸프로필기, n-헥실기, 시클로헥실기, 1-메틸펜틸기, 2-메틸펜틸기, 1,1-디메틸부틸기, 1,3-디메틸부틸기, 헵틸기, 시클로헵틸기, 옥틸기, 시클로옥틸기, 노닐기, 데실기, 운데실기, 도데실기, 아다만틸기 등을 구체예로 들 수 있다.In this specification, an alkyl group having 1 to 12 carbon atoms, which may be linear, branched or cyclic, represents a linear, branched or cyclic hydrocarbon group consisting of 1 to 12 carbon atoms, for example, a methyl group, an ethyl group, n-propyl group, i-propyl group, cyclopropyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, 1-methyl Butyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, n-hexyl group, Cyclohexyl group, 1-methylpentyl group, 2-methylpentyl group, 1,1-dimethylbutyl group, 1,3-dimethylbutyl group, heptyl group, cycloheptyl group, octyl group, cyclooctyl group, nonyl group, de Specific examples include a practical group, an undecyl group, a dodecyl group, and an adamantyl group.
치환될 수 있는 탄소 원자 6 내지 12의 방향족기로는, 할로겐 원자, 탄소 원자 수 1 내지 12의 알킬기, 시아노기, 니트로기, 탄소 원자 수 1 내지 12의 알킬카르보닐기, 탄소 원자 수 1 내지 12의 알킬옥시기, 디(탄소 원자 수 1 내지 12의 알킬)아미노기 등에서 선택되는 동일 또는 서로 다른 1개 이상의 치환기로 치환될 수 있는 페닐기, 나프틸기 등을 들 수 있다.Examples of the aromatic group having 6 to 12 carbon atoms which may be substituted include a halogen atom, an alkyl group having 1 to 12 carbon atoms, a cyano group, a nitro group, an alkylcarbonyl group having 1 to 12 carbon atoms, and an alkyl having 1 to 12 carbon atoms. A phenyl group, a naphthyl group, etc. which may be substituted by the same or different 1 or more substituents chosen from an oxy group, a di (alkyl of 1-12 carbon atoms), etc. are mentioned.
치환될 수 있는 탄소 원자 수 2 내지 6의 아실기로는, 불소 원자, 염소 원자, 취소 원자, 옥소 원자, 니트로기, 시아노기 등에서 선택되는 동일 또는 서로 다른 1개 이상의 치환기로 치환될 수 있는 메틸카르보닐기, 에틸카르보닐기, n-프로필카르보닐기, i-프로필카르보닐기, n-부틸카르보닐기, i-부틸카르보닐기, sec-부틸카르보닐기, t-부틸카르보닐기, n-펜틸카르보닐기 등을 들 수 있다.As the acyl group having 2 to 6 carbon atoms which may be substituted, a methylcarbonyl group which may be substituted with the same or different one or more substituents selected from a fluorine atom, a chlorine atom, a cancel atom, an oxo atom, a nitro group, a cyano group and the like And an ethylcarbonyl group, n-propylcarbonyl group, i-propylcarbonyl group, n-butylcarbonyl group, i-butylcarbonyl group, sec-butylcarbonyl group, t-butylcarbonyl group, n-pentylcarbonyl group and the like.
치환될 수 있는 탄소 원자 수 1 내지 6의 알콕시카르보닐기로는, 불소 원자, 염소 원자, 취소 원자, 옥소 원자, 니트로기, 시아노기 등에서 선택되는 동일 또는 서로 다른 1개 이상의 치환기로 치환될 수 있는 메톡시카르보닐기, 에톡시카르보닐기, n-프로필옥시카르보닐기, i-프로필옥시카르보닐기, n-부틸옥시카르보닐기, i-부틸옥시카르보닐기, sec-부틸옥시카르보닐기, t-부틸옥시카르보닐기, n-펜틸옥시카르보닐기 n-헥실옥시카르보닐기 등을 들 수 있다.Examples of the alkoxycarbonyl group having 1 to 6 carbon atoms which may be substituted include meth, which may be substituted with the same or different one or more substituents selected from a fluorine atom, a chlorine atom, a cancellation atom, an oxo atom, a nitro group, a cyano group, and the like. Oxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, i-propyloxycarbonyl group, n-butyloxycarbonyl group, i-butyloxycarbonyl group, sec-butyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group n- Hexyloxycarbonyl group etc. are mentioned.
방향환부가 치환될 수 있는 벤질기로는, 방향족부가 할로겐 원자, 탄소 원자 수 1 내지 12인 알킬기, 시아노기, 니트로기, 탄소 원자 수 1 내지 12인 알킬카르 보닐기, 탄소 원자 수 1 내지 12인 알킬옥시기, 디(탄소 원자 수 1 내지 12의 알킬)아미노기 등에서 선택되는 동일 또는 서로 다른 1개 이상의 치환기로 치환될 수 있는 벤질기를 나타낸다.Examples of the benzyl group in which the aromatic ring may be substituted include a halogen atom, an alkyl group having 1 to 12 carbon atoms, a cyano group, a nitro group, an alkylcarbonyl group having 1 to 12 carbon atoms, and a carbon atom having 1 to 12 carbon atoms. Benzyl group which can be substituted by the same or different 1 or more substituents chosen from an alkyloxy group, a di (alkyl of 1-12 carbon atoms), etc. are shown.
방향환부가 치환될 수 있는 벤질옥시카르보닐기로는, 방향족부가 할로겐 원자, 탄소 원자 수 1 내지 12인 알킬기, 시아노기, 니트로기, 탄소 원자 수 1 내지 12인 알킬카르보닐기, 탄소 원자 수 1 내지 12인 알킬옥시기, 디(탄소 원자 수 1 내지 12의 알킬)아미노기 등에서 선택되는 동일 또는 서로 다른 1개 이상의 치환기로 치환될 수 있는 벤질옥시카르보닐기를 나타낸다.Examples of the benzyloxycarbonyl group in which the aromatic ring may be substituted include a halogen atom, an alkyl group having 1 to 12 carbon atoms, a cyano group, a nitro group, an alkylcarbonyl group having 1 to 12 carbon atoms, and a carbon atom having 1 to 12 carbon atoms. Benzyloxycarbonyl group which may be substituted by the same or different one or more substituents selected from an alkyloxy group, a di (alkyl having 1 to 12 carbon atoms) and the like.
[R2 및 R3는 이들이 결합하는 질소 원자와 함께 환을 형성한다]는, R2 및 R3가 이들이 결합하는 질소 원자와 함께, 피페리딘환, 피롤리딘환, 숙신이미드환, 말레이미드환 등을 형성하는 것을 의미한다.[R <2> and R <3> forms a ring with the nitrogen atom to which they couple | bond, "R <2> and R <3> together with the nitrogen atom to which they couple | bond together, a piperidine ring, a pyrrolidine ring, a succinimide ring, a maleimide It means forming a ring or the like.
이하, 바람직한 치환기는 다음과 같다.Hereinafter, preferable substituents are as follows.
바람직한 R1 및 R4로는, 각각 독립적으로 메틸기, 에틸기, n-프로필기, i-프로필기, n-부틸기, i-부틸기, sec-부틸기, t-부틸기, 벤질기 등을 들 수 있다.As preferable R <1> and R <4> , a methyl group, an ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, benzyl group etc. are mentioned each independently. Can be.
또한, 바람직한 R2로는, 수소 원자, 메틸기, 에틸기, n-프로필기 등을 들 수 있다.Moreover, as preferable R <2> , a hydrogen atom, a methyl group, an ethyl group, n-propyl group, etc. are mentioned.
또한, 바람직한 R3로는, 벤질기, 벤질옥시카르보닐기, 아세틸기, t-부틸옥시카르보닐기 등을 들 수 있다.Moreover, as preferable R <3> , a benzyl group, benzyl oxycarbonyl group, an acetyl group, t-butyloxy carbonyl group, etc. are mentioned.
또한, 바람직한 X로는, 염소, 취소 및 옥소 등을 들 수 있다.Moreover, as preferable X, chlorine, cancellation, oxo, etc. are mentioned.
이하, 더욱 상세히 본 발명을 설명한다.Hereinafter, the present invention will be described in more detail.
즉, 식(1)로 나타내는 아미노마론산 유도체와 식(2)로 나타내는 α-할로아세트아미드를 용매에 혼합하고, 여기에 염기를 첨가함으로써 아미노마론산 유도체의 α위를 알킬화한다. 그렇게 하면 계 중에서 빠르게 고리화가 생기고, 식(3)에서 나타내는 숙신이미드 화합물을 제조할 수 있다. 식(3) 중의 R5는 식(1) 중의 R1, R4, 또는 결과적으로 계 중의 알콜과 에스테르 교환한 것 중 어느 하나이다. 한편, R1과 R4가 다른 치환기인 경우에는, 혼합물을 첨가할 수 있으므로, 이를 회피하는 의미에서는 R1과 R4는 같은 치환기인 것이 바람직하다.That is, the alpha position of an aminomaronic acid derivative is alkylated by mixing the aminomaronic acid derivative represented by Formula (1) and the alpha-haloacetamide represented by Formula (2) in a solvent, and adding a base to it. By doing so, a cyclization rapidly arises in a system, and the succinimide compound shown by Formula (3) can be manufactured. R <5> in Formula (3) is either R <1> , R <4> in Formula (1), or consequently, transesterified with the alcohol in the system. On the other hand, when R 1 and R 4 are different substituents, a mixture can be added, so that R 1 and R 4 are preferably the same substituent in the sense of avoiding this.
α-할로아세트아미드로는, 예를 들어, α-클로로아세트아미드, α-브로모아세트아미드, α-요오드아세트아미드를 사용할 수 있으나, 바람직하게는 α-브로모아세트아미드, α-요오드아세트아미드, 보다 바람직하게는 α-요오드아세트아미드가 사용된다. 또한 이 경우, 계 중에서 할로겐 교환에 의해 조제된 α-요오드아세트아미드를 사용하여도 좋다.As the α-haloacetamide, for example, α-chloroacetamide, α-bromoacetamide and α-iodine acetamide may be used, but preferably α-bromoacetamide and α-iodine acetamide More preferably α-iodineacetamide is used. In this case, alpha -iodineacetamide prepared by halogen exchange in the system may be used.
사용하는 염기로는, 예를 들어, 나트륨에톡시드, 칼륨에톡시드, 나트륨메톡시드, 칼륨메톡시드, 칼륨t-부톡시드, 나트륨펜톡시드 등의 알칼리금속 알콕시드를 들 수 있으나, 바람직하게는, 나트륨에톡시드 및 나트륨메톡시드를 들 수 있다. 염기의 선택에서는, 에스테르 교환이 바람직하지 않은 경우에는, 예를 들어 에틸에스테르에는 나트륨에톡시드를 선택하는 것이 바람직하다.Examples of the base to be used include alkali metal alkoxides such as sodium ethoxide, potassium ethoxide, sodium methoxide, potassium methoxide, potassium t-butoxide, sodium pentoxide, and the like. Examples thereof include sodium ethoxide and sodium methoxide. In the case of base selection, when transesterification is not preferable, for example, it is preferable to select sodium ethoxide for ethyl ester.
사용하는 용매로는, 예를 들어, 에탄올, 메탄올, n-프로판올, 이소프로판올 등의 알콜을 들 수 있으나, 바람직하게는, 에탄올, 메탄올을 들 수 있다. 용매의 선택에서는, 에스테르 교환이 바람직하지 않은 경우에는 예를 들어, 에틸에스테르에는 에탄올을 선택하는 것이 바람직하다.Examples of the solvent used may include alcohols such as ethanol, methanol, n-propanol, isopropanol, and preferably ethanol and methanol. In the selection of the solvent, when transesterification is not preferred, for example, ethanol is preferably selected for ethyl ester.
또한, 용매는 반응에 관여하지 않으면 그 외의 용매(톨루엔, 헥산, 초산에틸 등)와의 혼합물이어도 좋다.In addition, a solvent may be a mixture with other solvent (toluene, hexane, ethyl acetate, etc.), if it does not participate in reaction.
염기의 사용량은, 식(1)로 나타내는 아미노마론산 에스테르 화합물에 대해 1 내지 10당량, 바람직하게는 1.5 내지 3당량, 보다 바람직하게는 1.8 내지 2.5당량이다.The use amount of base is 1 to 10 equivalents, preferably 1.5 to 3 equivalents, more preferably 1.8 to 2.5 equivalents, relative to the aminomaronic acid ester compound represented by formula (1).
용매의 사용량은, 식(1)로 나타내는 아미노마론산 에스테르 화합물에 대해 1 내지 200질량부 사용할 수 있고, 바람직하게는 3 내지 20질량부의 범위이다.The usage-amount of a solvent can use 1-200 mass parts with respect to the aminomaronic acid ester compound represented by Formula (1), Preferably it is the range of 3-20 mass parts.
식(2)로 나타내는 화합물(α-할로아세트아미드)의 사용량은, 식(1)로 나타내는 아미드마론산 에스테르화합물에 대해 0.5 내지 10당량, 바람직하게는 1 내지 2당량이다.The usage-amount of the compound ((alpha) -haloacetamide) shown by Formula (2) is 0.5-10 equivalent, Preferably it is 1-2 equivalent with respect to the amidemaronic acid ester compound shown by Formula (1).
반응 온도는 통상 -20℃부터 사용하는 용매의 끓는점 까지의 온도 범위 내이 고, 바람직하게는 -10 내지 20℃의 온도 범위 내, 더욱 바람직하게는 -10 내지 10℃의 온도 범위 내이다.The reaction temperature is usually in the temperature range from -20 ° C to the boiling point of the solvent used, preferably in the temperature range of -10 to 20 ° C, more preferably in the temperature range of -10 to 10 ° C.
시약을 첨가하는 순서는 앞의 나열에 한정되는 것은 아니다.The order of adding the reagents is not limited to the above list.
한편, 본 발명에서 한정된 염기와 용매의 조합 이외의 조건으로 유사한 반응을 행한 경우에는 순차 반응을 억제하는 것이 곤란하고, 식(5)On the other hand, when similar reactions are carried out under conditions other than the combination of the base and the solvent defined in the present invention, it is difficult to sequentially suppress the reactions.
로 나타내는 순차 반응 생성물이 대량으로(대부분의 경우, 식(3)으로 나타내는 목적물 이상으로)생성된다.The sequential reaction products represented by are produced in large quantities (in most cases, beyond the target product represented by formula (3)).
그러나, 본 발명의 반응 조건이면, 순차 반응을 10% 이하, 최적 조건이면 2% 이하로 억제할 수 있고, 고선택적으로 고수율로 목적물의 식(3)으로 나타내는 숙신이미드 화합물을 얻을 수 있다.However, under the reaction conditions of the present invention, the succinimide compound represented by Formula (3) of the target product can be obtained in high yield at high yield, with the sequential reaction being 10% or less, and the optimum condition. .
반응에 의해 얻어진 식(3)으로 나타내는 숙신이미드 화합물은, 예를 들어 반응 종료 후, 산으로 퀀칭한 후, 적당한 용매에 의해 추출하고, 수세함으로써 얻을 수 있고, 또한 필요에 따라, 재결정, 증류, 실리카겔 컬럼크로마토그래피 등에 의해 정제할 수 있다.The succinimide compound represented by Formula (3) obtained by the reaction can be obtained by, for example, quenching with an acid after completion of the reaction, followed by extraction with an appropriate solvent and washing with water. And silica gel column chromatography.
다음 실시예를 들어, 본 발명의 내용을 구체적으로 설명하지만, 본 발명은 이에 한정되는 것은 아니다.For the following examples, the content of the present invention will be described in detail, but the present invention is not limited thereto.
한편, 식(4)로 나타내는 숙신이미드 화합물의 정량 수율은, 역상계고속액체 크로마토그래피를 이용하여, p-t-부틸페놀을 내부 표준 물질로 하는 정량 분석을 행하는 것에 의해 결정하였다.In addition, the quantitative yield of the succinimide compound represented by Formula (4) was determined by performing quantitative analysis which uses p-t-butylphenol as an internal standard substance using reverse phase high performance liquid chromatography.
컬럼: XBridge C18(워터즈 제)Column: XBridge C18 (made by Waters)
전개 용매: 물/아세트니트릴/초산=58/42/0.1(용적비)Developing solvent: water / acetonitrile / acetic acid = 58/42 / 0.1 (volume ratio)
오븐 온도: 40℃Oven Temperature: 40 ℃
검출법: UV210nmDetection method: UV210nm
실시예 1: 2-벤질옥시카르보닐아미노-2-에톡시카르보닐숙신이미드의 제조Example 1 Preparation of 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide
에탄올 45g에 α-요오드아세트아미드 10.4g(56.2mmol)을 첨가하고, 2-벤질옥시카르보닐아미노마론산디에틸의 70% 톨루엔 용액 21.4g(48.2mmol)을 첨가하여, 0℃로 냉각하였다. 여기에 나트륨에톡시드의 20% 에탄올 용액 33.0g(97.0mmol)을 0℃로 유지한 채로 1시간 적하하였다. 0℃에서 3시간 교반하고, 반응액을 정량한 결과, 2-벤질옥시카르보닐아미노-2-에톡시카르보닐숙신이미드가 13.7g(수율 89%) 생성되었다.10.4 g (56.2 mmol) of α-iodine acetamide was added to 45 g of ethanol, and 21.4 g (48.2 mmol) of a 70% toluene solution of diethyl 2-benzyloxycarbonylaminomaronic acid was added thereto, followed by cooling to 0 ° C. 33.0 g (97.0 mmol) of 20% ethanol solution of sodium ethoxide was dripped at this for 1 hour, maintaining 0 degreeC. It stirred at 0 degreeC for 3 hours, and quantified the reaction liquid, and produced 13.7g (yield 89%) of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide.
실시예 2: 2-벤질옥시카르보닐아미노-2-에톡시카르보닐숙신이미드의 제조Example 2: Preparation of 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide
에탄올 123kg에 요오드화나트륨 25.0kg(167mol), α-클로로아세트아미드 14.2kg(152mol)을 첨가하고, 77℃로 승온하여, 3시간 교반하였다. 이 현탁액에 2-벤질옥시카르보닐아미노마론산디에틸의 69% 톨루엔 용액 58.2kg(130mol)을 첨가하여, 0℃로 냉각하였다. 여기에 나트륨에톡시드의 20% 에탄올 용액 89.1kg(262mol)을 0℃로 유지한 채로 3시간 적하하였다. 0℃에서 3시간 교반한 후, 초산 7.9kg, 85% 인산 15.1kg을 첨가하여 퀀칭하고, 용매를 감압 유거하여 톨루엔 200kg과 물 80kg을 첨가하여 분액하였다. 유기층을 3회 수세한 후 정량 분석한 결과, 2-벤질옥시카르보닐아미노-2-에톡시카르보닐숙신이미드의 수율은 87.5%였다. 이 용액을 농축한 후, 톨루엔, 에탄올로 재결정하여 2-벤질옥시카르보닐아미노-2-에톡시카르보닐숙신이미드를 백색 결정으로 30kg(수율 72%) 얻었다.25.0 kg (167 mol) of sodium iodide and 14.2 kg (152 mol) of (alpha)-chloroacetamides were added to 123 kg of ethanol, it heated up at 77 degreeC, and stirred for 3 hours. 58.2 kg (130 mol) of 69% toluene solutions of diethyl 2-benzyloxycarbonylaminomaronic acid were added to this suspension, and it cooled to 0 degreeC. 89.1 kg (262 mol) of 20% ethanol solution of sodium ethoxide was dripped here for 3 hours, maintaining 0 degreeC. After stirring at 0 ° C. for 3 hours, 7.9 kg of acetic acid and 15.1 kg of 85% phosphoric acid were added and quenched, the solvent was distilled off under reduced pressure, and 200 kg of toluene and 80 kg of water were added for separation. The organic layer was washed with water three times and quantitatively analyzed, and the yield of 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide was 87.5%. The solution was concentrated and then recrystallized with toluene and ethanol to give 2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide as white crystals (30% yield 72%).
한편, 본 예에서 사용한 2-벤질옥시카르보닐아미노마론산디에틸은, 염기로 탄산나트륨을 이용하고, 2-아미노마론산디에틸염산염과 벤질옥시카르보닐클로리드에서 상법에 따라 합성하였다.On the other hand, diethyl 2-benzyloxycarbonylaminomaronic acid used in the present example was synthesized by using a sodium carbonate as a base, and according to the conventional method, in 2-aminomaronic acid diethyl hydrochloride and benzyloxycarbonyl chloride.
본 발명의 제조 방법은, 의약품 등의 중간 원료로 유용한 숙신이미드 화합물의 고효율적인 제조 방법을 제공하는 것이다.The manufacturing method of this invention provides the high efficiency manufacturing method of the succinimide compound useful as intermediate raw materials, such as a pharmaceutical.
본 발명의 제조 방법에 의하면, 의약품 등의 중간 원료로 유용한 숙신이미드 화합물을 저가로 단공정이면서 안전하게 제조할 수 있다.According to the production method of the present invention, a succinimide compound useful as an intermediate raw material such as pharmaceuticals can be manufactured safely at a low cost in a short step.
또한, 본 발명의 제조 방법에 의하면, 기존의 제조 방법 보다도 고수율로 숙 신이미드 화합물을 제조할 수 있다.Moreover, according to the manufacturing method of this invention, a succinimide compound can be manufactured with higher yield than the existing manufacturing method.
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| JP2006262249 | 2006-09-27 | ||
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| KR1020097005322A KR20090057388A (en) | 2006-09-27 | 2007-09-26 | Method for producing succinimide compound |
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| US (1) | US7807846B2 (en) |
| EP (1) | EP2077261A4 (en) |
| JP (1) | JP5149803B2 (en) |
| KR (1) | KR20090057388A (en) |
| CN (1) | CN101516843B (en) |
| WO (1) | WO2008050570A1 (en) |
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| KR101494868B1 (en) * | 2013-11-19 | 2015-02-23 | 한화케미칼 주식회사 | Method and apparatus for preparing functionalized graphene and functionalized graphene |
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| TW202450B (en) * | 1991-06-26 | 1993-03-21 | Dainippon Pharmaceutical Co | |
| JP3158128B2 (en) | 1992-12-25 | 2001-04-23 | 大日本製薬株式会社 | Succinimide derivatives |
| AU1884595A (en) | 1994-04-29 | 1995-11-29 | Pfizer Inc. | Novel acyclic and cyclic amides as neurotransmitter release enhancers |
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| JPWO2008050570A1 (en) | 2010-02-25 |
| US7807846B2 (en) | 2010-10-05 |
| CN101516843A (en) | 2009-08-26 |
| EP2077261A4 (en) | 2010-04-14 |
| CN101516843B (en) | 2011-06-15 |
| US20100004464A1 (en) | 2010-01-07 |
| JP5149803B2 (en) | 2013-02-20 |
| WO2008050570A1 (en) | 2008-05-02 |
| EP2077261A1 (en) | 2009-07-08 |
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